Clefts of the lip and/or palate are common human birth defects that require substantial surgical, dental, speech, and behavioral interventions and impose economic and societal burdens. While there are many rare causes of clefting disorders, approximately 70% are isolated or nonsyndromic and the result of a complex interplay of genegene and gene-environment interactions. After more than a decade of etiologic investigations with relatively modest advances, the last two years has seen the field become excitingly dynamic. We have recently demonstrated significant contributions by the MSX1, FGFR1, and IRF6 genes to cases of nonsyndromic clefting and have just completed the first two of a three stage genome-wide search to identify genes for clefts. Linkage analysis has found three novel high probability loci (6q, 8p, gq) in 217 families with genotyping almost complete on an additional 53 families. One locus, on 9q, has a LOD of 6.6. Coupling these successes to a realistic capacity for high throughput genotyping and powerful new statistical approaches affords the opportunity to characterize genetic and gene-environmental causes of clefting with unprecedented power and resolution. In this proposal we will use a large collection of families (over 330) and case parent triads (over 950) from the Philippines as a core resource for genome wide linkage and disequilibrium studies. We supplement this core collection with collaborative access to over 600 families for linkage and over 2000 triads with extensive environmental exposure data. The specific aims of this proposal will use candidate gene rankings based on global human gene expression analysis to assist in fine mapping and gene identification. Dense SNP maps will be combined with conserved sequence elements identified by multiple species comparisons to select the best regions in which to begin mutation searches. Genes/mutations that are likely to be etiologic will undergo additional genetic evaluation and functional analysis. Characterization of genomic rearrangements will provide an adjunct to gene finding. Discovered genes will then be used in studies of gene-gene and gene-environment interactions. The outcome of this project will be immediate and direct contributions to understanding genetic aspects of clefting and far better insights into the basic biology of craniofacial development. It will confirm proof of principle that complex human birth defects can be understood, and diagnosis and prevention improved.